Means for detecting pathological transformation of the app protein and their uses

ABSTRACT

A method of intra-articular drug delivery may include selecting an attachment zone in a synovial joint; affixing a drug release device in the attachment zone, the drug release device comprising a base affixable in the attachment zone, a sustained-release drug carrier, and a drug, the device positioned so that the device releases the drug into the synovial fluid of the synovial joint, and so that agitation of the synovial fluid facilitates elution of the drug from the drug release device.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/536,135, filed Jan. 13, 2004, and also claims the benefit of U.S.Provisional Application Ser. No. 60/566,737, filed Apr. 29, 2004. Theaforementioned patent applications are hereby incorporated herein bythis reference.

INTRODUCTION

Pain and disability from arthritis, joint degeneration, and surgery havebeen treated by a combination of oral medications or intra-articularinjections of steroid compounds designed to reduce inflammation. Inaddition, other devices, such as hyaluronic acid products, have beeninjected to provide visco-supplementation. Unfortunately, theseapproaches have significant systemic side effects or are not effectivefor extended periods of time.

In order to provide local or regional blockade for extended periods,clinicians currently use local anesthetics administered through acatheter or syringe to a site where the pain is to be blocked. Thisrequires repeated administration where the pain is to be blocked over aperiod of greater than one day, either as a bolus or through anindwelling catheter connected to an infusion pump. These methods havethe disadvantage of potentially causing irreversible damage to nerves orsurrounding tissues due to fluctuations in concentration and high levelsof anesthetic. In addition, anesthetic administered by these methods aregenerally neither confined to the target area, nor delivered in alinear, continuous manner. In all cases, analgesia rarely lasts forlonger than six to twelve hours, more typically four to six hours. Inthe case of a pump, the infusion lines are difficult to position andsecure, the patient has limited, encumbered mobility and, when thepatient is a small child or mentally impaired, they may accidentallydisengage the pump.

In part, this disclosure describes implantable devices that may be usedto deliver drugs to a joint.

SUMMARY

In one aspect, this disclosure describes devices and methods fordelivering drugs to the synovial fluid of a joint by locally implantinga drug delivery device. In certain embodiments, the device is positionedin such a way that agitation of synovial fluid facilitates elution ofthe drug from the device.

In one aspect, a method of intra-articular drug delivery includesselecting an attachment zone in a synovial joint and affixing a drugrelease device in the attachment zone. Exemplary suitable attachmentzones include intra-articular regions of the synovial joint where thereis no interfacing articular cartilage. In certain instances, anattachment zone may include intra-articular regions of bone that arenon-load-bearing and optionally removed from the articulation surface.In certain embodiments, the drug release device includes a baseaffixable in the attachment zone, a sustained-release drug carrier, anda drug. The device may be positioned, in certain applications, so thatthe device releases the drug into the synovial fluid of the synovialjoint, and further, so that agitation of the synovial fluid mayfacilitate elution of the drug from the drug release device.

In a further aspect, a method of providing a therapeutic to a skeletalarticulation includes identifying a safe zone of the articulation andcoupling a therapeutic elution apparatus in the safe zone. Exemplarysafe zones include non-load-bearing regions in or around thearticulation. In certain embodiments, the therapeutic elution apparatusincludes a body couplable in the safe zone, and a therapeutic dispersedin a controlled-release binder. The apparatus may be positioned, incertain applications, so that it releases the therapeutic into thearticulation environment.

In another aspect, a drug delivery device includes a base and asustained-release drug carrier coupled to the base. In certainembodiments, the base may be so sized and shaped as to be capable ofaffixation in an attachment zone of a synovial joint. Typically, thecarrier includes a drug to be eluted in vivo, often into the synovialfluid upon implantation of the device in a joint. In certainapplications, the carrier may be so formed as to elute the drug intosynovial fluid sufficient to sustain a therapeutically effectiveconcentration of the drug in the synovial fluid for at least 8 hours.

In yet another aspect, a wide range of therapeutic drugs arecontemplated, including but limited to antiinflammatories,antiinfectives, analgesics, and anesthetics. A wide range of drugcarrier materials are contemplated, including but not limited topolymers, such as polytetrafluoroethylene, polyfluorinatedethylenepropylene, polylactic acid, polyglycolic acid, silicone, andmixtures thereof.

In still another aspect, a drug delivery device may be delivered by awide variety of methods, such as by placement into a drill site, orforceful injection by gun. In an embodiment, a method of intra-articulardrug delivery may include selecting an attachment zone in a synovialjoint, and affixing a drug release device in the attachment zone, thedrug release device comprising a base affixable in the attachment zone,a sustained-release drug carrier, and a drug, the device positioned sothat the device releases the drug into the synovial fluid of thesynovial joint, and so that agitation of the synovial fluid facilitateselution of the drug from the drug release device.

In any preceding embodiment, the attachment zone may include anon-articulating portion of bone and/or cartilage within the synovialjoint.

Any preceding embodiment may further include removing the bone and/orcartilage in the attachment zone to create a void, and so inserting thedrug release device into the void that at least one surface of the drugrelease device is in communication with the synovial fluid.

In any preceding embodiment, the drug release device may be so insertedthat its surface in communication with the synovial fluid is about flushwith surrounding bone and/or cartilage.

In any preceding embodiment, the attachment zone may include a band ofbone and/or cartilage adjacent to an articulating surface within thesynovial joint.

In any preceding embodiment, the band may extend from about 0.5millimeters to about 1 centimeter away from the articulating surface.

In any preceding embodiment, the synovial joint may be a hip joint, andthe attachment zone may include a non-articulating portion of boneand/or cartilage within the hip.

In any preceding embodiment, the attachment zone may include a band ofbone and/or cartilage adjacent to at least one of a femoral head, and anacetabulum.

In any preceding embodiment, the synovial joint may be a knee joint, andthe attachment zone may include a non-articulating portion of boneand/or cartilage within the knee.

In any preceding embodiment, the attachment zone may include a band ofbone and/or cartilage adjacent to at least one of a tibial plateau, afemoral condyle, a patellofemoral area, the medial rim of a femoraltrochlea, the lateral rim of a femoral trochlea, and the periphery of anintercondylar notch.

In any preceding embodiment, the synovial joint may be a shoulder joint,and the attachment zone comprises a non-articulating portion of boneand/or cartilage within the shoulder.

In any preceding embodiment, the attachment zone may include a band ofbone and/or cartilage adjacent to at least one of the anatomical neck ofa humerus, a glenoid cavitym and a glenoid neck.

In any preceding embodiment, the synovial joint may be an arthroplasticjoint comprising at least one prosthesis, and the attachment zonecomprises a non-articulating portion of bone and/or cartilage within thejoint.

In any preceding embodiment, wherein the attachment zone may include aband of bone and/or cartilage adjacent to the at least one prosthesis.

In any preceding embodiment, the drug release device may be forcefullyinjected by gun.

In any preceding embodiment, the drug release device may include threadson its outer surface, and the drug release device may be affixed bydrilling a hole in the attachment zone and screwing the drug releasedevice into the hole.

In any preceding embodiment, the drug release device may include a base,so sized and shaped as to be affixable in an attachment zone of asynovial joint, and a sustained-release drug carrier coupled to thebase, the carrier including a drug, the carrier so formed as to elutethe drug into synovial fluid, upon implantation of the device in ajoint, sufficient to sustain a therapeutically effective concentrationof the drug in the synovial fluid for at least 8 hours.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a cross section of an exemplary intra-articular drugdelivery device.

FIG. 2 depicts an exemplary positioning of an intra-articular drugdelivery device.

FIG. 3 depicts a cross section of a generalized synovial joint.

FIG. 4 depicts a cross section of a knee joint showing exemplaryplacements of an intra-articular drug delivery device.

FIGS. 5-8 depict various synovial joints and exemplary placements of anintra-articular drug delivery device therein.

FIGS. 9-11A depict exemplary drug delivery devices and components.

FIGS. 12-13 depict exemplary placements of drug delivery devices.

FIG. 14 depicts an exemplary insertion device for a drug deliverydevice.

FIGS. 15-17 depict various synovial joints and exemplary placements ofan intra-articular drug delivery device therein.

FIG. 18 depicts an exemplary placements of an intra-articular drugdelivery device in the context of arthroplasty.

DETAILED DESCRIPTION

1. Overview

The present disclosure provides devices and methods for delivering drugsto joints, particularly synovial joints. In part, this disclosureprovides controlled-release devices that are capable of being implantedin the joint to deliver therapeutic agents, often to the synovial fluid.In certain examples, the devices, when implanted, are capable ofproviding sustained drug release of therapeutic agents into the synovialfluid of the affected joint for the relief of pain, reduction ofinflammation, the enhancement of joint lubrication, the treatment ofinfection, and/or the treatment or prevention of other diseases orconditions.

In a preferred embodiment, a device is implanted within a joint intobone in an area that is substantially exposed to synovial fluid flow,preferably allowing sustained elution of the therapeutic compound intothe synovial fluid and a substantially even distribution of the desiredtherapeutic within the joint. In certain instances, the implantationsite is constantly exposed to synovial fluid flow.

Each joint contains specified areas defined hereafter as “attachmentzones” that permit drilling, anchoring, or other types of affixing of adevice. Certain attachment zones will not cause substantial damage tothe load-bearing or articulating cartilage or other surfaces of thespecified joint. In certain embodiments, the placement and location ofthe device does not cause material damage to the cartilage surface, asit may placed and secured using an anchoring device that fixes thedevice to bone, in the joint cavity, but not into or on the articulatingsurface of the joint in a manner that could cause such damage while thedevice is in place.

The controlled release devices may be biocompatible and may be capableof being implanted or otherwise placed into a joint. In an exemplaryembodiment, a device may have a core including a drug/polymercomposition and an outer layer along the long axis of the device that issubstantially impermeable to the entrance of an environmental fluid andsubstantially impermeable to the release of the drug during a deliveryperiod, with drug release possible across a short axis plane of thedevice, which axis or end of the device may be exposed to synovial fluidupon placement. In certain instances, the end of the device may have asemipermeable membrane or alternatively it may expose the core directly.In certain instances, the short axis plane of a device may account for aminority, such as no more than about 10%, no more than about 20%, nomore than about 30%, no more than about 40%, or less than 50%, of thetotal surface area of the device. The device can be so sized and shaped,and formed of such materials, as to facilitate delivering a variety ofdrugs with varying degrees of solubility and molecular weight. Methodsare also provided for using these drug delivery devices.

In certain aspects, the devices may be implanted in regions of a jointthat are non-load-bearing and/or that do not form part of thecartilaginous articulation surfaces of bones. In further examples, thedevices may be anchored to and recessed within bone either fully or inpart. In certain instances, usually when recessed fully, the portion ofthe device's surface exposed to the synovial fluid is substantiallyflush with the bone surface. In still further embodiments, the devicesmay be positioned in a joint so that agitation of synovial fluid past orthrough the exposed surface facilitates elution of a therapeuticincorporated in the device. In other examples, the one or moretherapeutics may be formulated for sustained release, such as byimpregnating them in a matrix, or mixing them with a suitablecomposition, such as a polymer.

2. Definitions

For convenience, before further description of exemplary embodiments,certain terms employed in the specification, examples, and appendedclaims are collected here. These definitions should be read in light ofthe remainder of the disclosure and understood as by a person of skillin the art.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “access device” is an art-recognized term and includes anymedical device adapted for gaining or maintaining access to an anatomicarea Such devices are familiar to artisans in the medical and surgicalfields. An access device may be a needle, a catheter, a cannula, atrocar, a tubing, a shunt, a drain, or an endoscope such as an otoscope,nasopharyngoscope, bronchoscope, or any other endoscope adapted for usein the joint area, or any other medical device suitable for entering orremaining positioned within the preselected anatomic area.

The terms “biocompatible polymer” and “biocompatibility” when used inrelation to polymers are art-recognized. For example, biocompatiblepolymers include polymers that are generally neither themselves toxic tothe host, nor degrade (if the polymer degrades) at a rate that producesmonomeric or oligomeric subunits or other byproducts at toxicconcentrations in the host. In certain embodiments, biodegradationgenerally involves degradation of the polymer in a host, e.g., into itsmonomeric subunits, which may be known to be effectively non-toxic.Intermediate oligomeric products resulting from such degradation mayhave different toxicological properties, however, or biodegradation mayinvolve oxidation or other biochemical reactions that generate moleculesother than monomeric subunits of the polymer. Consequently, in certainembodiments, toxicology of a biodegradable polymer intended for in vivouse, such as implantation or injection into a patient, may be determinedafter one or more toxicity analyses. It is not necessary that anysubject composition have a purity of 100% to be deemed biocompatible;indeed, it is only necessary that the subject compositions bebiocompatible as set forth above. Hence, a subject composition maycomprise polymers comprising 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75%or even less of biocompatible polymers, e.g., including polymers andother materials and excipients described herein, and still bebiocompatible.

To determine whether a polymer or other material is biocompatible, itmay be necessary to conduct a toxicity analysis. Such assays are wellknown in the art. One example of such an assay may be performed withlive carcinoma cells, such as GT3TKB tumor cells, in the followingmanner: the sample is degraded in 1M NaOH at 37° C. until completedegradation is observed. The solution is then neutralized with 1M HCl.About 200 μL of various concentrations of the degraded sample productsare placed in 96-well tissue culture plates and seeded with humangastric carcinoma cells (GT3TKB) at 10⁴/well density. The degradedsample products are incubated with the GT3TKB cells for 48 hours. Theresults of the assay may be plotted as % relative growth vs.concentration of degraded sample in the tissue-culture well. Inaddition, polymers and formulations may also be evaluated by well-knownin vivo tests, such as subcutaneous implantations in rats to confirmthat they do not cause significant levels of irritation or inflammationat the subcutaneous implantation sites.

The term “biodegradable” is art-recognized, and includes polymers,compositions and formulations, such as those described herein, that areintended to degrade during use. Biodegradable polymers typically differfrom non-biodegradable polymers in that the former may be degradedduring use. In certain embodiments, such use involves in vivo use, suchas in vivo therapy, and in other certain embodiments, such use involvesin vitro use. In general, degradation attributable to biodegradabilityinvolves the degradation of a biodegradable polymer into its componentsubunits, or digestion, e.g., by a biochemical process, of the polymerinto smaller, non-polymeric subunits. In certain embodiments, twodifferent types of biodegradation may generally be identified. Forexample, one type of biodegradation may involve cleavage of bonds(whether covalent or otherwise) in the polymer backbone. In suchbiodegradation, monomers and oligomers typically result, and even moretypically, such biodegradation occurs by cleavage of a bond connectingone or more of subunits of a polymer. In contrast, another type ofbiodegradation may involve cleavage of a bond (whether covalent orotherwise) internal to side chain or that connects a side chain to thepolymer backbone. For example, a therapeutic agent or other chemicalmoiety attached as a side chain to the polymer backbone may be releasedby biodegradation. In certain embodiments, one or the other or bothgenerally types of biodegradation may occur during use of a polymer. Asused herein, the term “biodegradation” encompasses both general types ofbiodegradation.

The degradation rate of a biodegradable polymer often depends in part ona variety of factors, including the chemical identity of the linkageresponsible for any degradation, the molecular weight, crystallinity,biostability, and degree of cross-linking of such polymer, the physicalcharacteristics of the implant, shape and size, and the mode andlocation of administration. For example, the greater the molecularweight, the higher the degree of crystallinity, and/or the greater thebiostability, the biodegradation of any biodegradable polymer is usuallyslower. The term “biodegradable” is intended to cover materials andprocesses also termed “bioerodible”.

In certain embodiments, if the biodegradable polymer also has atherapeutic agent or other material associated with it, thebiodegradation rate of such polymer may be characterized by a releaserate of such materials. In such circumstances, the biodegradation ratemay depend on not only the chemical identity and physicalcharacteristics of the polymer, but also on the identity of any suchmaterial incorporated therein.

In certain embodiments, polymeric formulations biodegrade within aperiod that is acceptable in the desired application. In certainembodiments, such as in vivo therapy, such degradation occurs in aperiod usually less than about five years, one year, six months, threemonths, one month, fifteen days, five days, three days, or even one dayon exposure to a physiological solution with a pH between 6 and 8 havinga temperature of between 25 and 37° C. In other embodiments, the polymerdegrades in a period of between about one hour and several weeks,depending on the desired application.

The terms “comprise,” “comprising,” “include,” “including,” “have,” and“having” are used in the inclusive, open sense, meaning that additionalelements may be included. The terms “such as”, “e.g.”, as used hereinare non-limiting and are for illustrative purposes only. “Including” and“including but not limited to” are used interchangeably.

The term “drug delivery device” is an art-recognized term and refers toany medical device suitable for the application of a drug to a targetedorgan or anatomic region. The term includes those devices that transportor accomplish the instillation of the compositions towards the targetedorgan or anatomic area, even if the device itself is not formulated toinclude the composition. As an example, a needle or a catheter throughwhich the composition is inserted into an anatomic area or into a bloodvessel or other structure related to the anatomic area is understood tobe a drug delivery device. As a further example, a stent or a shunt or acatheter that has the composition included in its substance or coated onits surface is understood to be a drug delivery device. A drug deliverydevice can include a rigid or flexible container. It may include asemi-solid composition that release drug by dissolution of the device orby leaching of drug from the device. We should also be clear that“implant” covers attaching to the joint in any way, e.g., by implantinginto a cavity in bone or cartilage or by suturing or otherwise adheringthe device to the surface of bone, tendon, or cartilage.

When used with respect to a therapeutic agent or other material, theterm “sustained release” is art-recognized. For example, a subjectcomposition that releases a substance over time may exhibit sustainedrelease characteristics, in contrast to a bolus type administration inwhich the entire amount of the substance is made biologically availableat one time. For example, in particular embodiments, upon contact withbody fluids including blood, tissue fluid, lymph or the like, thepolymer matrices (formulated as provided herein and otherwise as knownto one of skill in the art) may undergo gradual degradation (e.g.,through hydrolysis) with concomitant release of any materialincorporated therein, for a sustained or extended period (as compared tothe release from a bolus). This release may result in prolonged deliveryof therapeutically effective amounts of any incorporated a therapeuticagent. Sustained release will vary in certain embodiments as describedin greater detail below.

The term “delivery agent” is an art-recognized term, and includesmolecules that facilitate the intracellular delivery of a therapeuticagent or other material. Examples of delivery agents include: sterols(e.g., cholesterol) and lipids (e.g., a cationic lipid, virosome orliposome).

The term “or” as used herein should be understood to mean “and/or”,unless the context clearly indicates otherwise.

The phrases “parenteral administration” and “administered parenterally”are art-recognized terms, and include modes of administration other thanenteral and topical administration, such as injections, and include,without limitation, intravenous, intramuscular, intrapleural,intravascular, intrapericardial, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The term “treating” is art-recognized and includes preventing a disease,disorder or condition from occurring in an animal which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder or condition, e.g., causing regression of the disease, disorderand/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected.

The term “fluid” is art-recognized to refer to a non-solid state ofmatter in which the atoms or molecules are free to move in relation toeach other, as in a gas or liquid. If unconstrained upon application, afluid material may flow to assume the shape of the space available toit, covering for example, the surfaces of an excisional site or the deadspace left under a flap. A fluid material may be inserted or injectedinto a limited portion of a space and then may flow to enter a largerportion of the space or its entirety. Such a material may be termed“flowable.” This term is art-recognized and includes, for example,liquid compositions that are capable of being sprayed into a site;injected with a manually operated syringe fitted with, for example, a23-gauge needle; or delivered through a catheter. Also included in theterm “flowable” are those highly viscous, “gel-like” materials at roomtemperature that may be delivered to the desired site by pouring,squeezing from a tube, or being injected with any one of thecommercially available injection devices that provide injectionpressures sufficient to propel highly viscous materials through adelivery system such as a needle or a catheter. When the polymer used isitself flowable, a composition comprising it need not include abiocompatible solvent to allow its dispersion within a body cavity.Rather, the flowable polymer may be delivered into the body cavity usinga delivery system that relies upon the native flowability of thematerial for its application to the desired tissue surfaces. Forexample, if flowable, a composition comprising polymers can be injectedto form, after injection, a temporary biomechanical barrier to coat orencapsulate internal organs or tissues, or it can be used to producecoatings for solid implantable devices. In certain instances, flowablesubject compositions have the ability to assume, over time, the shape ofthe space containing it at body temperature.

Viscosity is understood herein as it is recognized in the art to be theinternal friction of a fluid or the resistance to flow exhibited by afluid material when subjected to deformation. The degree of viscosity ofthe polymer may be adjusted by the molecular weight of the polymer andother methods for altering the physical characteristics of a specificpolymer will be evident to practitioners of ordinary skill with no morethan routine experimentation. The molecular weight of the polymer usedmay vary widely, depending on whether a rigid solid state (highermolecular weights) desirable, or whether a fluid state (lower molecularweights) is desired.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting any subject composition from one organ, or portion of thebody, to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof a subject composition and not injurious to the patient. In certainembodiments, a pharmaceutically acceptable carrier is non-pyrogenic.Some examples of materials which may serve as pharmaceuticallyacceptable carriers include: (1) sugars, such as lactose, glucose andsucrose; (2) starches, such as corn starch and potato starch; (3)cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5)malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter andsuppository waxes; (9) oils, such as peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10)glycols, such as propylene glycol; (11) polyols, such as glycerin,sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyloleate and ethyl laurate; (13) agar; (14) buffering agents, such asmagnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19)ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxiccompatible substances employed in pharmaceutical formulations.

The term “pharmaceutically acceptable salts” is art-recognized, andincludes relatively non-toxic, inorganic and organic acid addition saltsof compositions, including without limitation, therapeutic agents,excipients, other materials and the like. Examples of pharmaceuticallyacceptable salts include those derived from mineral acids, such ashydrochloric acid and sulfuric acid, and those derived from organicacids, such as ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, and the like. Examples of suitable inorganicbases for the formation of salts include the hydroxides, carbonates, andbicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium,aluminum, zinc and the like. Salts may also be formed with suitableorganic bases, including those that are non-toxic and strong enough toform such salts. For purposes of illustration, the class of such organicbases may include mono-, di-, and trialkylamines, such as methylamine,dimethylamine, and triethylamine; mono-, di- or trihydroxyalkylaminessuch as mono-, di-, and triethanolamine; amino acids, such as arginineand lysine; guanidine; N-methylglucosamine; N-methylglucamine;L-glutamine; N-methylpiperazine; morpholine; ethylenediamine;N-benzylphenethylamine; (trihydroxymethyl)aminoethane; and the like.See, for example, J. Pharm. Sci., 66:1-19 (1977).

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as primates, mammals,and vertebrates.

The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “synovial joint” refers to a moveable articulation of two ormore bones. The articulation is defined by a synovial cavity, whichcontains a volume of synovial fluid, is lined with a synovial membrane,and is surrounded by a fibrous capsule. The opposing bone surfaces areeach covered with a layer of cartilage. The cartilage and synovial fluidreduce friction between the articulating bone surfaces and enable smoothmovements. Synovial joints can be further distinguished by their shape,which controls the movements they allow. For example, hinge joints actlike the hinge on a door, allowing flexion and extension in just oneplane. An example is the elbow between the humerus and the ulna. Balland socket joints, such as the hip, allow movement in several planessimultaneously. Condyloid (or ellipsoid) joints, such as the knee,permit motion in more than one plane in some positions but not others.For example, no rotation is possible in the extended knee, but somerotation is possible when the knee is flexed. Pivot joints, such as theelbow (between the radius and the ulna), allow one bone to rotate aroundanother. Saddle joints, such as at the thumb (between the metacarpal andcarpal) are so named because of their saddle shape, and allow movementin a variety of directions. Finally, gliding joints, such as in thecarpals of the wrist, allow a wide variety of movement, but not muchdistance.

Synovial joints include but are not limited to shoulder (glenohumeraland acromioclavicular), elbow (ulno-humeral, radio-capitellar andproximal radioulnar), forearm (radioulnar, radiocarpal, ulnocarpal),wrist (distal radioulnar, radio-carpal, ulno-carpal, mid carpal), hand(carpo-metacarpal, metocarpophalangeal, interphalangeal), spine(intervertebral), hip, knee, ankle (tibiotalar, tibiofibular), and foot(talocalcaneal, talonavicular, intertarsal, tarso-metatarsal,metatarsal-phalangeal, interphalangeal).

The terms “therapeutic agent”, “drug”, “medicament” and “bioactivesubstance” are art-recognized and include molecules and other agentsthat are biologically, physiologically, or pharmacologically activesubstances that act locally or systemically in a patient or subject totreat a disease or condition, such as joint pain, degeneration,inflammation, or infection. The terms include without limitation,medicaments; vitamins; mineral supplements; substances used for thetreatment, prevention, diagnosis, cure or mitigation of disease orillness; or substances which affect the structure or function of thebody; or pro-drugs, which become biologically active or more activeafter they have been placed in a predetermined physiologicalenvironment.

Such agents may be acidic, basic, or salts; they may be neutralmolecules, polar molecules, or molecular complexes capable of hydrogenbonding; they may be prodrugs in the form of ethers, esters, amides andthe like that are biologically activated when administered into apatient or subject.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a therapeuticagent that, when incorporated into a polymer, produces some desiredeffect at a reasonable benefit/risk ratio applicable to any medicaltreatment. In certain embodiments, the term refers to that amountnecessary or sufficient to eliminate, reduce or maintain (e.g., preventthe spread of) a tumor or other target of a particular therapeuticregimen. The effective amount may vary depending on such factors as thedisease or condition being treated, the particular targeted constructsbeing administered, the size of the subject or the severity of thedisease or condition. One of ordinary skill in the art may empiricallydetermine the effective amount of a particular compound withoutnecessitating undue experimentation.

The term “preventing”, when used in relation to a condition, such as alocal recurrence, a disease such as cancer, a syndrome complex such asheart failure or any other medical condition, is well understood in theart, and includes administration of a composition which reduces thefrequency of, or delays the onset of, symptoms of a medical condition ina subject relative to a subject which does not receive the composition.Thus, prevention of cancer includes, for example, reducing the number ofdetectable cancerous growths in a population of patients receiving aprophylactic treatment relative to an untreated control population,and/or delaying the appearance of detectable cancerous growths in atreated population versus an untreated control population, e.g., by astatistically and/or clinically significant amount. Prevention of aninfection includes, for example, reducing the number of diagnoses of theinfection in a treated population versus an untreated controlpopulation, and/or delaying the onset of symptoms of the infection in atreated population versus an untreated control population.

“Radiosensitizer” is defined as a therapeutic agent that, uponadministration in a therapeutically effective amount, promotes thetreatment of one or more diseases or conditions that are treatable withelectromagnetic radiation. In general, radiosensitizers are intended tobe used in conjunction with electromagnetic radiation as part of aprophylactic or therapeutic treatment. Appropriate radiosensitizers touse in conjunction with treatment with the subject compositions will beknown to those of skill in the art.

“Electromagnetic radiation” as used in this specification includes, butis not limited to, radiation having the wavelength of 10⁻²⁰ to 10meters. Particular embodiments of electromagnetic radiation employ theelectromagnetic radiation of: gamma-radiation (10⁻²⁰ to 10⁻¹³ m), x-rayradiation (10⁻¹¹ to 10⁻⁹ m), ultraviolet light (10 nm to 400 nm),visible light (400 nm to 700 nm), infrared radiation (700 nm to 1.0 mm),and microwave radiation (1 mm to 30 cm).

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” areart-recognized, and include the administration of a subject compositionor other material at a site remote from the disease being treated.Administration of an agent directly into, onto or in the vicinity of alesion of the disease being treated, even if the agent is subsequentlydistributed systemically, may be termed “local” or “topical” or“regional” administration, other than directly into the central nervoussystem, e.g., by subcutaneous administration, such that it enters thepatient's system and, thus, is subject to metabolism and other likeprocesses.

In certain embodiments, a therapeutically effective amount of atherapeutic agent for in vivo use will likely depend on a number offactors, including: the rate of release of the agent from the polymermatrix, which will depend in part on the chemical and physicalcharacteristics of the polymer; the identity of the agent; the mode andmethod of administration; and any other materials incorporated in thepolymer matrix in addition to the agent.

The term “ED₅₀” is art-recognized. In certain embodiments, ED₅₀ meansthe dose of a drug which produces 50% of its maximum response or effect,or alternatively, the dose which produces a pre-determined response in50% of test subjects or preparations. The term “LD₅₀” is art-recognized.In certain embodiments, LD₅₀ means the dose of a drug which is lethal in50% of test subjects. The term “therapeutic index” is an art-recognizedterm which refers to the therapeutic index of a drug, defined asLD₅₀/ED₅₀.

The terms “incorporated” and “encapsulated” are art-recognized when usedin reference to a therapeutic agent and a polymeric composition, such asa composition disclosed herein. In certain embodiments, these termsinclude incorporating, formulating or otherwise including such agentinto a composition which allows for sustained release of such agent inthe desired application. The terms may contemplate any manner by which atherapeutic agent or other material is incorporated into a polymermatrix, including for example: attached to a monomer of such polymer (bycovalent or other binding interaction) and having such monomer be partof the polymerization to give a polymeric formulation, distributedthroughout the polymeric matrix, appended to the surface of thepolymeric matrix (by covalent or other binding interactions),encapsulated inside the polymeric matrix, etc. The term“co-incorporation” or “co-encapsulation” refers to the incorporation ofa therapeutic agent or other material and at least one other atherapeutic agent or other material in a subject composition.

More specifically, the physical form in which a therapeutic agent orother material is encapsulated in polymers may vary with the particularembodiment. For example, a therapeutic agent or other material may befirst encapsulated in a microsphere and then combined with the polymerin such a way that at least a portion of the microsphere structure ismaintained. Alternatively, a therapeutic agent or other material may besufficiently immiscible in a controlled-release polymer that it isdispersed as small droplets, rather than being dissolved, in thepolymer. Any form of encapsulation or incorporation is contemplated bythe present disclosure, in so much as the sustained release of anyencapsulated therapeutic agent or other material determines whether theform of encapsulation is sufficiently acceptable for any particular use.

The term “biocompatible plasticizer” is art-recognized, and includesmaterials which are soluble or dispersible in the controlled-releasecompositions described herein, which increase the flexibility of thepolymer matrix, and which, in the amounts employed, are biocompatible.Suitable plasticizers are well known in the art and include thosedisclosed in U.S. Pat. Nos. 2,784,127 and 4,444,933. Specificplasticizers include, by way of example, acetyl tri-n-butyl citrate (c.20 weight percent or less), acetyl trihexyl citrate (c. 20 weightpercent or less), butyl benzyl phthalate, dibutyl phthalate,dioctylphthalate, n-butyryl tri-n-hexyl citrate, diethylene glycoldibenzoate (c. 20 weight percent or less) and the like.

“Small molecule” is an art-recognized term and refers to a moleculewhich has a molecular weight of less than about 2000 amu, or less thanabout 1000 amu, and even less than about 500 amu.

3. Implant Structure

A wide variety of structures may be employed for providing drug deliveryto synovial joints. Typically, a drug delivery device may include a basethat is so sized and shaped as to be affixable in the synovial joint,and a drug carrier coupled to the base that includes a therapeutic drug.

An exemplary implantable intra-articular drug delivery device isdepicted in FIG. 1. As shown in this exemplary embodiment, the base ofthe device may include a housing (5), and the drug carrier may include amass (4). The mass (4) may be disposed inside the housing. In someinstances, the mass (4) may be a cartridge. For example, the cartridgemay be manufactured separately from the housing and later inserted intothe housing. The cartridge or mass (4) may be replaceable, so that thedrug carrier may be removed from the device without disturbing thehousing's affixation in a joint

The outer layer of the mass (4) may be formed at least in part by amaterial substantially impermeable to the drug and/or environmentalfluids (such as synovial fluid in a joint). The material may include apolymer. Examples of polymers include polytetrafluoroethylene,polyfluorinated ethylenepropylene, polylactic acid, polyglycolic acid,silicone, and mixtures thereof.

The mass (4) may have a surface (1) exposed to the environment, such assynovial fluid. The surface (1) may be covered at least in part by amembrane, such as a semi-permeable membrane. The membrane may be formedto prevent particulate materials, such as biodegradable polymer, frompassing out of the drug carrier and into the synovial fluid, whilepermitting the drug released from the carrier (2) to pass out of thecartridge and in to the joint. This filter may take consist of asemi-permeable, osmotic membrane or a porous cellulose filter such as aMillipore filter.

In certain embodiments, the housing (5) may be made at least in part ofa biocompatible material. Furthermore, in some embodiments, the housing(5) may be made of an implantable material, such as a material suitablefor implantation in bone, implantation in cartilage, and/or implantationin other biomaterials in a joint. In certain embodiments, the housing isformed at least in part of a material of sufficient strength to beimplanted into bone without damage. In particular, the housing may beformed at least in part of a material that can maintain the housing'sintegrity during implantation. This may help prevent leakage of a drugin the carrier through a crack or fissure in the housing. In someembodiments, the reservoir housing may be constructed from a metal, suchas titanium, nickel titanium, stainless steel, anodized aluminum, ortantalum, or a plastic, such as polyethylene, nylon, or polyurethane.Alternatively a composite or ceramic may be used. The housing may alsoinclude a material or modified material to allow for osseous integrationof the implant—i.e., bone ingrowth. Other suitable materials will beapparent to one of ordinary skill in the art. Moreover, combinations ofmaterials may be used.

In certain embodiments, the device may be affixable in an attachmentzone of a joint. As depicted in FIG. 1, the housing (5) may include oneor more barbs (3). The barb or barbs (3) may lodge in and/or against,for example, a bony surface, and thereby minimize the device's motionrelative to the bone. In some embodiments, barbs (3) may be axiallyaligned. They may be circumferentially spaced in relation to each otherabout the base.

In some embodiments, the barb or barbs may be able to adopt differentstates; in some states, the barbs may be retracted or otherwise disposedto facilitate mobility and positioning of the device; in other states,the barbs may be expanded or otherwise disposed to facilitate lodgmentand immobility of the device. The barb or barbs may be transitionablebetween one or more such states. For example, a barb may have a first,or “retracted” state, in which the barb's span lies close enough to thedevice as not to impede positioning the device. The barb may have asecond, or “expanded” state, in which the barb's free end so protrudesfrom the device as to impinge surrounding anatomy, thereby promotingaffixation of the device.

In some embodiments, the barb may be deformable among various states.For example, a barb may be biased toward a particular state. A barb maybe constrained to an unbiased state and allowed to assume a biased statewhen the constraint is removed. In some embodiments, a constraint may bemechanical, such as a sleeve or an adhesive. In some embodiments, aconstraint may be chemical, so that the barb changes configuration inresponse to a chemical reaction. In some embodiments, the barb may havea shape memory. A shape memory may be dependent, for example, ontemperature. In one embodiment, a barb may assume a “retracted” statebelow attachment zone temperature and an “expanded” state at attachmentzone temperature, so that disposition of a device in an attachment zonecauses the barb to transition from the retracted state to the expandedstate. A barb may be elastically or plastically deformable; a barb maybe reversibly or irreversible deformable.

In the embodiment depicted in FIG. 1, the barbs extend rearwardly andradially outwardly from the body. In some embodiments, the barb end(s)may extend to positions outside a longitudinal projection of the largestgeometric cross-section of the body transverse to its longitudinal axis.

Barbs (3) may be formed at least in part by a wide variety of materials.Examples include materials disclosed in U.S. Pat. No. 4,665,906 entitled“Medical Devices Incorporating SIM Alloy Elements”, issued May 19, 1987to Jervis. Other exemplary materials are nickel-titanium alloys, such asnitinol. The combination of the material and orientation of the barbs onthe reservoir housing can help the barbs to “spring back” toward theirnormal, unstressed condition after the insertion process of the deviceinto bone, for example, is complete.

The device may include other features to make it affixable in anattachment zone of a joint. For example, the base may have a variablediameter. The device may adopt a first diameter to facilitate insertion,and a second diameter to facilitate affixation. The device may beprovided with an adhesive, such as bone cement, that promotes adhesionof the device to the material of the attachment zone. The device may beprovided with cells, growth factors, cytokines, or other biomaterials topromote infiltration and anchoring of the device by host tissue.

The device of this exemplary embodiment may be embedded in a bone suchthat the device's surface is flush with the surrounding bone, and sothat the semipermeable membrane faces the synovial cavity. A schematicdepiction of this orientation is shown in FIG. 2. The device may be thuspositioned so as not to present an obstruction for potentialinterference with joint motion. Furthermore, when so positioned, thedevice may be exposed to synovial fluid through the semipermeablemembrane. Thus, as synovial fluid flows over the membrane, diffusion oftherapeutic agent may occur. In addition, synovial fluid can infiltratethe device through the membrane and thus provide fluid communication forthe agent to reach the synovial fluid.

In preferred embodiments, a sustained drug delivery device forintraarticular use may have a cross-sectional diameter in the range ofabout 0.5 mm to about 5 mm. It may have a length in the range of about 3mm to about 20 mm.

Other structures are contemplated. In one exemplary embodiment, thedevice includes a base coated with the drug carrier. In anotherexemplary embodiment, the device may be so sized and shaped to be aprosthetic replacement for all or a portion of a bone. For example, thedevice base may be a portion of a femur used in a total kneereplacement. Many other examples of bone prosthetics will be readilyapparent to one of ordinary skill in the art. The drug carrier iscoupled to the base as described above. Alternatively, the prostheticbase can define a recess into which a drug carrier, such as a modularcartridge, may be placed.

FIGS. 9-11 depict other embodiments of drug delivery devices. In oneembodiment, the device 10 may include a stage/housing 11. The stage 11may be externally threaded. The external threads can help keep the stagein position. For example, the threaded stage could be screwed into apre-drilled hole in an attachment zone. Alternatively, the device couldbe inserted in a self boring/self tapping manner, in the recipientattachment zone. The stage may include a tip, such as a sharpened tip15, suitable for this purpose.

FIG. 11 a shows another embodiment of a drug delivery device. Thehousing may include an outer threaded surface and inner threaded orsmooth surface. The housing may define an inner cavity. A plug ofdrug/polymer mixture may be placed the cavity. The inner threads on thehousing facilitate anchoring the plug and may also facilitate removaland exchange of a cartridge with the drug polymer mixture.

FIG. 12 shows some exemplary placements of threaded devices, similar tothose shown in FIG. 4.

The stage 11 may also include a central socket 12. The central socketmay be threaded. A drug implant 13 may be disposed in the central socket12. The implant 13 may have the same or similar shape as the socket 12to help it remain in position. For example, the implant can be moldedwith threads on its body to match the recipient threads of the socket ofthe stage. The threads may be machined to have a thread interval or“pitch” of about 0.25 mm to 1.5 mm and can vary to about 0.1 mm to 0.25mm at the lower end of the implant. The threads may have flat top landswith a nominal width of about 0.10 mm to 0.15 mm.

The implant 13 can be removed and/or replaced when it has degraded, whenthe drug is degraded, exhausted, or being delivered in subtherapeuticconcentration, or when the need or desirability has passed for theparticular drug being eluted. The insert may be held in the stage by theaforementioned threading. In one embodiment, a differential thread pitchcan be provided to “lock” the insert in place, to preclude loosening andescape into the joint space

In certain embodiments, the device can have an outer diameter in therange of about 1 mm to about 10 mm. In certain embodiments, the devicecan have a length of about 3 mm to about 2 cm.

As shown in FIG. 13, The cap of the drug/polymer insert may include arounded surface 14. This surface can reduce physical interaction withsurrounding soft tissue. This surface can also expose an adequatesurface for drug elution and desired pharmacokinetic release.

4. Attachment Zones

As discussed above, each joint contains specified areas definedhereafter as “attachment zones” that permit drilling, anchoring, orother types of affixing of a device. Certain attachment zones will notcause substantial damage to the load-bearing or articulating cartilageor other surfaces of the specified joint. In certain embodiments, theplacement and location of the device does not cause material damage tothe cartilage surface, as it may be placed and secured using ananchoring device that fixes the device to bone, in the joint cavity, butnot into or on the articulating surface of the joint in a manner thatcould cause such damage while the device is in place.

In some embodiments, an attachment zone may be an intra-articular regionof a synovial joint where there is no interfacing articular cartilage.It may be located, for example, in a bone portion that isnon-load-bearing and removed from the articulation surface of thesynovial joint. The device may be attached at an attachment zone withinthe synovial joint, allowing for continuous exposure to synovial fluidflow and resulting release of therapeutic, without damaging thearticular surface that is in apposition during range of motion of thegiven joint.

FIG. 3 shows one example of an attachment zone in a synovial joint. Thejoint depicted is an idealized synovial joint but roughly approximatesthe femur-tibia articulation at the knee. An exemplary attachment zoneis indicated by the bracket. In this example, the indicated attachmentzone is located in the joint and is remote from the load-bearingportions of the bone and also from the articulating surfaces of thebones. Although the zone may include portions of the bone withcartilage, the cartilage is not interfacing cartilage, i.e., does notform part of the articulation surface of the joint.

FIG. 4 shows exemplary placements of drug delivery devices in thedepicted attachment zone. In accordance with the attachment zone exampleshown in FIG. 3, the device may be placed in a non-load-bearing andnon-articulating portion of the bone. As suggested in FIG. 4, more thanone device may be implanted in a single joint.

Attachment zones exist in every synovial joint. A joint may have morethan one attachment zone, and attachment zones may noncontiguous (i.e.,they may be regions of the joint isolated from each other). FIGS. 5-8depict examples of attachment zones in the shoulder, elbow, hip, andwrist/thumb joints, respectively. As shown in FIG. 5, attachment zonesin the shoulder joint can be in the area of redundant capsule mediallyand inferiorly. As shown in FIG. 6, attachment zones in the elbow can beat the distal aspect of the medial or lateral epicondyle superior to thetrochlea and capitellum respectively, or just distal to the radial headon the neck of the radius. As shown in FIG. 7, a hip attachment zoneexists just distal to the femoral head in the femoral neck. In FIG. 8,wrist and thumb (carpometacarpal) attachment zones are shown on the ulnaat the distal aspect of the distal radioulnar joint, at the distalaspect of the radial styloid, and at the base of the first metacarpal.Other joints, such as various interfaces in the ankle, also havesuitable attachment zones.

FIGS. 15-17 depict additional exemplary placements for drug deliverydevices. The attachment zones indicated in the figures includingnonarticulating regions of articular cartilage or bone. They may be saidto be “para-articular” because they are located just outside theportions of articular cartilage that receive the articulating load. Forexample, FIG. 15, like FIG. 3, shows an idealized synovial joint thatroughly approximates the knee articulation. The indicated attachmentzones are identified as those portions of the articular cartilage thatdo not bear weight. Many synovial joints include articular cartilagethat is non-load-bearing. A portion of non-load-bearing cartilage, then,can be removed in order to place a drug delivery device without harmingthe joint's load-bearing capacity, overall function, or health.

Portions of bone just beyond the non-load-bearing articulating cartilagecan also be selected as attachment zones. An advantage of selecting anattachment zone illustrated in FIGS. 15-17 is that these attachmentzones are as close as possible to the articulating surfaces of the jointwithout interfering with articulation. As a result, they are exposed torelatively robust synovial fluid circulation compared to the recesses ofthe joint where the synovial membrane folds back on itself. They arealso more accessible by various surgical and minimally-invasivetechniques for implantation, exchange, and/or removal. Another advantageis that regions of bone or cartilage nearer the articulation are lesslikely to become scarred or otherwise inaccessible following trauma orarthritic episodes in the joint.

Nonarticulating articular cartilage, as it might be called, can be foundin the knee joint at both the tibial plateau and the femoral condyles,as well as in the patellofemoral area, the medial rim of the femoraltrochlea, the lateral rim of the femoral trochlea, and the periphery ofthe intercondylar notch.

FIG. 16 depicts an exemplary shoulder joint and indicates somepara-articular attachment zones. An attachment zone on the humerus maybe found in a band just inferior to the anatomical neck, while anattachment zone on the scapula may be found around the ridge of theglenoid cavity or the glenoid neck.

FIG. 17 depicts an exemplary hip joint and indicates some para-articularattachment zones. An attachment zone on the femur is a band justinferior to the femoral head, while a para-articular attachment zone onthe hip bone may be found in a band just around the rim of theacetabulum. This figure shows that articulating cartilage extends justpast the margin of the acetabulum. The cartilage extending past themargin is para-articular because it does not touch the head of the femurand so does not bear a load.

FIG. 18 depicts exemplary attachment zones in a joint that has beensubjected to arthroplasty. When the natural para-articular cartilageand/or bone is removed, new attachment zones may be defined innon-articulating areas adjacent the prosthetic surfaces. As shown inFIG. 18 for a hip arthroplasty, attachments zones are defined as rimssurrounding the prostheses. For example, a hip attachment zone islocated in band adjacent the outer edge of the prosthetic acetabularcup, while a femoral attachment zone is located in a band around theprosthetic femoral stem. In an arthroplastic shoulder joint, attachmentzones may be defined on the humerus as a band surrounding the humeralstem, and on the scapula in a band adjacent the outer edge of a glenoidcomponent. In an arthroplastic knee, attachment zones may be defined onthe femur as a band surrounding the femoral component of the kneereplacement, and on the tibia as a band surrounding the tibial tray ofthe replacement.

When a bone is spared in an arthroplasty, the attachment zone may bedefined as that of the native bone. In some cases, however, such apartial arthroplasty may change which portions of articulating cartilagebear weight. In that case, the para-articular attachment zone will bedefined in a band around the articulating surface of the implant.

A drug delivery device may be implanted contemporaneously witharthroplasty. Benefits of contemporaneous fitting may be theforestalling, diminishing, or prevention of inflammation, infection,pain, etc., depending on which drugs are included in the drug deliverydevice. In one embodiment, a drug delivery device can be seated in thebone cement used to affix the prosthesis. Such seating would place thedevice in a very close but still para-articular position and would alsoeliminate the need for drilling a hole in bone.

The para-articular bands may vary widely in size and extent, dependingon the joint and upon the anatomy and shape of the subject. Apara-articular attachment zone may extend away from an articulatingsurface as much as about 1 cm, or as little as 5 mm, 4 mm, 3 mm, 2 mm, 1mm, or about 0.5 mm.

An attachment zone can be selected in a variety of ways. In oneembodiment, an image may be obtained of a bone or joint, such as aradiograph, a CT scan, an MRI, or other modality. The articulatingsurfaces can be identified by observing which portions of the subjectbones are apposed. An attachment zone, such as one depicted in FIGS.3-8, or a para-articular attachment zone, as depicted in FIGS. 15-18,may then be selected. The boundaries of a para-articular attachment zonecan be identified by measuring an appropriate distance from the edge ofan articulating surface. An attachment zone may be selected duringarthroscopy or an open procedure by direct visualization of thearticulating and non-articulating surfaces.

5. Therapeutic Agents

Possible biologically active agents include without limitation,medicaments; vitamins; mineral supplements; substances used for thetreatment, prevention, diagnosis, cure or mitigation of disease orillness; or substances that affect the structure or function of thebody.

The therapeutic agents are used in amounts that are therapeuticallyeffective, which varies widely depending largely on the particular agentbeing used. The amount of agent incorporated into the composition alsodepends upon the desired release profile, the concentration of the agentrequired for a biological effect, and the length of time that thebiologically active substance has to be released for treatment. Incertain embodiments, the biologically active substance may be blendedwith a polymer matrix at different loading levels, in one embodiment atroom temperature and without the need for an organic solvent. In otherembodiments, the compositions may be formulated as microspheres.

There is no critical upper limit on the amount of therapeutic agentincorporated except for that of an acceptable solution or dispersionviscosity to maintain the physical characteristics desired for thecomposition. The lower limit of the agent incorporated into the polymersystem is dependent upon the activity of the drug and the length of timeneeded for treatment. Thus, the amount of the agent should not be sosmall that it fails to produce the desired physiological effect, nor solarge that the agent is released in an uncontrollable manner. Typically,within these limits, amounts of the therapeutic agents from about 1% upto about 60% may be incorporated into the present delivery systems.However, lesser amounts may be used to achieve efficacious levels oftreatment for agent that are particularly potent.

Specific types of biologically active agents include, either directly orafter appropriate modification, without limitation: anti-angiogenesisfactors, antiinfectives such as antibiotics and antiviral agents;analgesics and analgesic combinations; anorexics; antihelmintics;antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants;antidiuretic agents; antidiarrheals; antihistamines; antiinflammatoryagents; antimigraine preparations; antinauseants; antineoplastics;antiparkinsonism drugs; antiproliferatives; antimitotics; antimetabolitecompounds; angiostatics; angiostatic steroids; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; catecholamines; diuretics;vasodilators including general coronary, peripheral and cerebral;central nervous system stimulants; cough and cold preparations,including decongestants; growth factors, hormones such as estradiol andother steroids, including corticosteroids; hypnotics;immunosuppressives; steroids; corticosteroids; glucocorticoids; musclerelaxants; parasympatholytics; psychostimulants; sedatives; andtranquilizers; and naturally derived or genetically engineered proteins,polysaccharides, glycoproteins, lipoproteins, interferons, cytokines,chemotherapeutic agents and other anti-neoplastics, antibiotics,anti-virals, anti-fungals, anti-inflammatories, anticoagulants,lymphokines, or antigenic materials.

To illustrate further, other types of biologically active agents thatmay be used, either directly or after appropriate modification, includepeptide, proteins or other biopolymers, e.g., interferons, interleukins,tumor necrosis factor, nerve growth factor (NGF), brain-derivedneurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5(NT-4/5), ciliary neurotrophic factor (CNTF), glial cell line-derivedneurotrophic factor (GDNF), cholinergic differentiation factor/Leukemiainhibitory factor (CDF/LIF), epidermal growth factor (EGF), insulin-likegrowth factor (IGF), basic fibroblast growth factor (bFGF),platelet-derived growth factor (PDGF), erythropoietin, growth hormone,Substance-P, neurotensin, insulin, erythropoietin, albumin, transferrin,and other protein biological response modifiers.

Other examples of biologically active agents that may be used eitherdirectly or after appropriate modification include acebutolol,acetaminophen, acetohydoxamic acid, acetophenazine, acyclovir,adrenocorticoids, allopurinol, alprazolam, aluminum hydroxide,amantadine, ambenonium, amiloride, aminobenzoate potassium, amobarbital,amoxicillin, amphetamine, ampicillin, androgens, anesthetics,anticoagulants, anticonvulsants-dione type, antithyroid medicine,appetite suppressants, aspirin, atenolol, atropine, azatadine,bacampicillin, baclofen, beclomethasone, belladonna,bendroflumethiazide, benzoyl peroxide, benzthiazide, benztropine,betamethasone, betha nechol, biperiden, bisacodyl, bromocriptine,bromodiphenhydramine, brompheniramine, buclizine, bumetanide, busulfan,butabarbital, butaperazine, caffeine, calcium carbonate, captopril,carbamazepine, carbenicillin, carbidopa & levodopa, carbinoxamineinhibitors, carbonic anhydsase, carisoprodol, carphenazine, cascara,cefaclor, cefadroxil, cephalexin, cephradine, chlophedianol, chloralhydrate, chlorambucil, chloramphenicol, chlordiazepoxide, chloroquine,chlorothiazide, chlorotrianisene, chlorpheniramine, 6× chlorpromazine,chlorpropamide, chlorprothixene, chlorthalidone, chlorzoxazone,cholestyramine, cimetidine, cinoxacin, clemastine, clidinium,clindamycin, clofibrate, clomiphere, clonidine, clorazepate,cloxacillin, colochicine, coloestipol, conjugated estrogen,contraceptives, cortisone, cromolyn, cyclacillin, cyclandelate,cyclizine, cyclobenzaprine, cyclophosphamide, cyclothiazide, cycrimine,cyproheptadine, danazol, danthron, dantrolene, dapsone,dextroamphetamine, dexamethasone, dexchlorpheniramine, dextromethorphan,diazepan, dicloxacillin, dicyclomine, diethylstilbestrol, diflunisal,digitalis, diltiazen, dimenhydrinate, dimethindene, diphenhydramine,diphenidol, diphenoxylate & atrophive, diphenylopyraline, dipyradamole,disopyramide, disulfiram, divalporex, docusate calcium, docusatepotassium, docusate sodium, doxyloamine, dronabinol ephedrine,epinephrine, ergoloidmesylates, ergonovine, ergotamine, erythromycins,esterified estrogens, estradiol, estrogen, estrone, estropipute,etharynic acid, ethchlorvynol, ethinyl estradiol, ethopropazine,ethosaximide, ethotoin, fenoprofen, ferrous fumarate, ferrous gluconate,ferrous sulfate, flavoxate, flecainide, fluphenazine, fluprednisolone,flurazepam, folic acid, furosemide, gemfibrozil, glipizide, glyburide,glycopyrrolate, gold compounds, griseofuwin, guaifenesin, guanabenz,guanadrel, guanethidine, halazepam, haloperidol, hetacillin,hexobarbital, hydralazine, hydrochlorothiazide, hydrocortisone(cortisol), hydroflunethiazide, hydroxychloroquine, hydroxyzine,hyoscyamine, ibuprofen, indapamide, indomethacin, insulin, iofoquinol,iron-polysaccharide, isoetharine, isoniazid, isopropamide isoproterenol,isotretinoin, isoxsuprine, kaolin & pectin, ketoconazole, lactulose,levodopa, lincomycin liothyronine, liotrix, lithium, loperamide,lorazepam, magnesium hydroxide, magnesium sulfate, magnesiumtrisilicate, maprotiline, meclizine, meclofenamate, medroxyproyesterone,melenamic acid, melphalan, mephenyloin, mephobarbital, meprobamate,mercaptopurine, mesoridazine, metaproterenol, metaxalone,methamphetamine, methaqualone, metharbital, methenamine, methicillin,methocarbamol, methotrexate, methsuximide, methyclothinzide,methylcellulos, methyldopa, methylergonovine, methylphenidate,methylprednisolone, methysergide, metoclopramide, metolazone,metoprolol, metronidazole, minoxidil, mitotane, monamine oxidaseinhibitors, nadolol, nafcillin, nalidixic acid, naproxen, narcoticanalgesics, neomycin, neostigmine, niacin, nicotine, nifedipine,nitrates, nitrofurantoin, nomifensine, norethindrone, norethindroneacetate, norgestrel, nylidrin, nystatin, orphenadrine, oxacillin,oxazepam, oxprenolol, oxymetazoline, oxyphenbutazone, pancrelipase,pantothenic acid, papaverine, para-aminosalicylic acid, paramethasone,paregoric, pemoline, penicillamine, penicillin, penicillin-v,pentobarbital, perphenazine, phenacetin, phenazopyridine, pheniramine,phenobarbital, phenolphthalein, phenprocoumon, phensuximide,phenylbutazone, phenylephrine, phenylpropanolamine, phenyl toloxamine,phenytoin, pilocarpine, pindolol, piper acetazine, piroxicam, poloxamer,polycarbophil calcium, polythiazide, potassium supplements, pruzepam,prazosin, prednisolone, prednisone, primidone, probenecid, probucol,procainamide, procarbazine, prochlorperazine, procyclidine, promazine,promethazine, propantheline, propranolol, pseudoephedrine, psoralens,psyllium, pyridostigmine, pyrodoxine, pyrilamine, pyrvinium, quinestrol,quinethazone, quinidine, quinine, ranitidine, rauwolfia alkaloids,riboflavin, rifampin, ritodrine, salicylates, scopolamine, secobarbital,senna, sannosides a & b, simethicone, sodium bicarbonate, sodiumphosphate, sodium fluoride, spironolactone, sucrulfate, sulfacytine,sulfamethoxazole, sulfasalazine, sulfinpyrazone, sulfisoxazole,sulindac, talbutal, tamazepam, terbutaline, terfenadine, terphinhydrate,teracyclines, thiabendazole, thiamine, thioridazine, thiothixene,thyroblobulin, thyroid, thyroxine, ticarcillin, timolol, tocainide,tolazamide, tolbutamide, tolmetin trozodone, tretinoin, triamcinolone,trianterene, triazolam, trichloromethiazide, tricyclic antidepressants,tridhexethyl, trifluoperazine, triflupromazine, trihexyphenidyl,trimeprazine, trimethobenzamine, trimethoprim, tripclennamine,triprolidine, valproic acid, verapamil, vitamin A, vitamin B-12, vitaminC, vitamin D, vitamin E, vitamin K, xanthine, parathyroid hormone,enkephalins, and endorphins.

To illustrate further, antimetabolites may be used as upon appropriatemodification if necessary, including without limitation methotrexate,5-fluorouracil, cytosine arabinoside (ara-C), 5-azacytidine,6-mercaptopurine, 6-thioguanine, and fludarabine phosphate. Antitumorantibiotics may include but are not limited to doxorubicin,daunorubicin, dactinomycin, bleomycin, mitomycin C, plicamycin,idarubicin, and mitoxantrone. Vinca alkaloids and epipodophyllotoxinsmay include, but are not limited to vincristine, vinblastine, vindesine,etoposide, and teniposide. Nitrosoureas, including carmustine,lomustine, semustine and streptozocin, may also be prodrugs, uponappropriate modification if necessary. Hormonal therapeutics may also beprodrugs, upon appropriate modification if necessary, such ascorticosteriods (cortisone acetate, hydrocortisone, prednisone,prednisolone, methyl prednisolone dexamethasone, and fluocinoloneacetonide), estrogens, (diethylstibesterol, estradiol, esterifiedestrogens, conjugated estrogen, chlorotiasnene), progestins(medroxyprogesterone acetate, hydroxy progesterone caproate, megestrolacetate), antiestrogens (tamoxifen), aromastase inhibitors(aminoglutethimide), androgens (testosterone propionate,methyltestosterone, fluoxymesterone, testolactone), antiandrogens(flutamide), LHRH analogues (leuprolide acetate), and endocrines forprostate cancer (ketoconazole). Antitumor drugs that are radiationenhancers may also be used as prodrugs, upon appropriate modification ifnecessary. Examples of such biologically active agents include, forexample, the chemotherapeutic agents 5′-fluorouracil, mitomycin,cisplatin and its derivatives, taxol, bleomycins, daunomycins, andmethamycins. Antibiotics may be used as prodrugs as well, uponappropriate modification if necessary, and they are well known to thoseof skill in the art, and include, for example, penicillins,cephalosporins, tetracyclines, ampicillin, aureothicin, bacitracin,chloramphenicol, cycloserine, erythromycin, gentamicin, gramacidins,kanamycins, neomycins, streptomycins, tobramycin, and vancomycin.

Other agents, upon appropriate modification if necessary, which may beused include those presently classified as investigational drugs, andcan include, but are not limited to alkylating agents such as NimustineAZQ, BZQ, cyclodisone, DADAG, CB10-227, CY233, DABIS maleate, EDMN,Fotemustine, Hepsulfam, Hexamethylmelamine, Mafosamide, MDMS, PCNU,Spiromustine, TA-077, TCNU and Temozolomide; antimetabolites, such asacivicin, Azacytidine, 5-aza-deoxycytidine, A-TDA, Benzylidene glucose,Carbetimer, CB3717, Deazaguanine mesylate, DODOX, Doxifluridine,DUP-785, 10-EDAM, Fazarabine, Fludarabine, MZPES, MMPR, PALA, PLAC,TCAR, TMQ, TNC-P and Piritrexim; antitumor antibodies, such as AMPAS,BWA770U, BWA773U, BWA502U, Amonafide, m-AMSA, CI-921, Datelliptium,Mitonafide, Piroxantrone, Aclarubicin, Cytorhodin, Epirubicin,esorubicin, Idarubicin, Iodo-doxorubicin, Marcellomycin, Menaril,Morpholino anthracyclines, Pirarubicin, and SM-5887; microtubule spindleinhibitors, such as Amphethinile, Navelbine, and Taxol; thealkyl-lysophospholipids, such as BM41-440, ET-18-OCH3, andHexacyclophosphocholine; metallic compounds, such as Gallium Nitrate,CL286558, CL287110, Cycloplatam, DWA2114R, NK121, Iproplatin,Oxaliplatin, Spiroplatin, Spirogermanium, and Titanium compounds; andnovel compounds such as, for example, Aphidoicolin glycinate, Ambazone,BSO, Caracemide, DSG, Didemnin, B, DMFO, Elsamicin, Espertatrucin,Flavone acetic acid, HMBA, HHT, ICRF-187, Iododeoxyuridine, Ipomeanol,Liblomycin, Lonidamine, LY186641, MAP, MTQ, Merabarone SK&F104864,Suramin, Tallysomycin, Teniposide, THU and WR2721; and Toremifene,Trilosane, and zindoxifene.

6. Controlled-Release or Sustained Release Compositions

In certain aspects, controlled-release compositions, upon contact withsynovial fluid, release the joint therapeutic over a sustained orextended period (as compared to the release from an isotonic salinesolution). Such a system may result in prolonged delivery (over, forexample, 2 to 4,000 hours, even 4 to 1500 hours) of effective amounts(e.g., 0.00001 mg/kg/hour to 10 mg/kg/hour) of the drug. This dosageform may be administered as is necessary depending on the subject beingtreated, the severity of the affliction, the judgment of the prescribingphysician, and the like.

For treatment of joints, controlled-release compositions are adapted forapplication to the joint. As used herein, the term “anatomic area”refers to an area of synovial joint anatomy, i.e., a joint thatfacilitates movement of the bones it articulates. In certainembodiments, the pharmaceutical compositions are understood to exerttheir effect in part by contact with a portion of the anatomic areabeing treated. Contact refers to a physical touching, either directlywith the subject composition being applied without intervening barrierto the anatomic area being treated, or indirectly, where the subjectcomposition is applied to or is formed on a surface of an interposedmaterial, passing through to come into direct contact with the anatomicarea being treated. Contact, as used herein, includes those situationswhere the pharmaceutical compounds are initially positioned to contactthe anatomic area being treated, and those situations where thecontrolled-release compositions are initially positioned in proximity tothe anatomic area being treated without contacting it, and subsequentlymove, migrate, flow, spread, or are transported to enter into contactwith the anatomic area being treated.

Contact may include partial contacts, wherein the pharmaceuticalcompounds only contact a portion of the anatomic area being treated, orthe edge or periphery or margin of the anatomic area being treated.Contact of the pharmaceutical compounds with the anatomic area beingtreated occurs from a local rather than systemic administration of saidcompounds, as these terms are defined hereinafter. The composition maybe formed as a flowable material, insertable into the anatomic area. Avariety of devices and methods for inserting the composition into thepreselected anatomic area will be familiar to practitioners of ordinaryskill in the art, for example infusion, injection, topical application,spraying, painting, coating, formed gel placement, and others. Thecomposition, alternatively, may be formed as a solid object implantablein the anatomic area, or as a film or mesh that may be used to cover asegment of the area. A variety of techniques for implanting solidobjects in relevant anatomic areas will be likewise familiar topractitioners of ordinary skill in the art.

Some examples of sustained release devices and compositions aredescribed in U.S. Pat. Nos. 5,618,563, 5,792,753, 5,942,241, 5,985,850,6,096,728, 6,214,387, 6,217,911, 6,248,345, 6,335,035, 6,346,519,6,426,339, 6,428,804, 6,451,335, 6,511,958, 6,514,514, 6,514,516,6,521,259, 6,524,606, 6,524,607, 6,527,760, 6,528,097, 6,528,107,6,534,081, 6,565,534, 6,582,715, 6,590,059, and 6,699,471; and in U.S.Patent Application Publication Nos. US 2003/0139811 A1 and US2003/0093157 A1; and in PCT Publication No. WO/0061152 A1. All of thesedocuments are hereby incorporated herein by this reference.

In some embodiments, the polymer composition may be a flexible orflowable material. When the polymer used is itself flowable, the polymercomposition, even when viscous, need not include a biocompatible solventto be flowable, although trace or residual amounts of biocompatiblesolvents may still be present.

In certain embodiments, a fluid polymer may be especially suitable forthe treatment of joint problems. A fluid material may be adapted forinjection or instillation into a tissue mass or into an actual orpotential space. Certain types of fluid polymers may be termed flowable.A flowable material, often capable of assuming the shape of the contoursof an irregular space, may be delivered to a portion of an actual orpotential space to flow therefrom into a larger portion of the space. Inthis way, the flowable material may come to coat an entirepost-operative surgical site after being inserted through an edge of anincision or after being instilled through a drain or catheter left inthe surgical bed. Alternatively, if the flowable material is insertedunder pressure through a device such as a needle or a catheter, it mayperform hydrodissection, thus opening up a potential space andsimultaneously coating the space with polymer. Such potential spacessuitable for hydrodissection may be found in various identifiableanatomic areas in joints. A flowable polymer may be particularly adaptedfor instillation through a needle, catheter or other delivery devicesuch as an endoscope, since its flowable characteristics allow it toreach surfaces that extend beyond the immediate reach of the deliverydevice. A flowable polymer in a highly fluid state may be suitable forinjection through needles or catheters into tissue masses, such astumors or margins of resection sites. Physical properties of polymersmay be adjusted to achieve a desirable state of fluidity or flowabilityby modification of their chemical components and crosslinking, usingmethods familiar to practitioners of ordinary skill in the art.

A flexible polymer may be used in the fabrication of a solid article.Flexibility involves having the capacity to be repeatedly bent andrestored to its original shape. Solid articles made from flexiblepolymers are adapted for placement in anatomic areas where they willencounter the motion of adjacent organs or body walls. Certain areas ofmotion are familiar to practitioners dealing with joint problems. Aflexible solid article can thus be sufficiently deformed by those movingtissues that it does not cause tissue damage. Flexibility isparticularly advantageous where a solid article might be dislodged fromits original position and thereby encounter an unanticipated movingstructure; flexibility may allow the solid article to bend out of theway of the moving structure instead of injuring it Solid articles may beformed as films, meshes, sheets, tubes, or any other shape appropriateto the dimensions and functional requirements of the particular anatomicarea. Physical properties of polymers may be adjusted to attain adesirable degree of flexibility by modification of the chemicalcomponents and crosslinking thereof, using methods familiar topractitioners of ordinary skill in the art.

While it is possible that the biocompatible polymer or the biologicallyactive agent may be dissolved in a small quantity of a solvent that isnon-toxic to more efficiently produce an amorphous, monolithicdistribution or a fine dispersion of the biologically active agent inthe flexible or flowable composition, it is an advantage that, in anembodiment, no solvent is needed to form a flowable composition.Moreover, the use of solvents may be avoided because, once a polymercomposition containing solvent is placed totally or partially within thebody, the solvent dissipates or diffuses away from the polymer and mustbe processed and eliminated by the body, placing an extra burden on thebody's clearance ability at a time when the illness (and/or othertreatments for the illness) may have already deleteriously affected it.

However, when a solvent is used to facilitate mixing or to maintain theflowability of the polymer composition, it should be non-toxic,otherwise biocompatible, and should be used in relatively small amounts.Solvents that are toxic clearly should not be used in any material to beplaced even partially within a living body. Such a solvent also must notcause substantial tissue irritation or necrosis at the site ofadministration.

Examples of suitable biocompatible solvents, when used, includeN-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol,acetone, methyl acetate, ethyl acetate, methyl ethyl ketone,dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam,dimethyl-sulfoxide, oleic acid, or 1-dodecylazacycloheptan-2-one. In oneembodiment, solvents include N-methyl-2-pyrrolidone, 2-pyrrolidone,dimethyl sulfoxide, and acetone because of their solvating ability andtheir biocompatibility.

The microspheres may be manufactured by incorporating the drug into thepolymer matrix by either dissolving or suspending the drug into polymersolution and the mixture will be subsequently dried by techniquesfamiliar to those skill in the arts to form microspheres. Thesetechniques include but not limited to spray drying, coating, variousemulsion methods and supercritical fluid processing. The microspheresmay be mixed with a pharmaceutically acceptable diluent prior to theadministration for injection. They may also be directly applied to thedesired site, such as a surgical wound or cavity, by various deliverysystems including pouring and spraying. The microspheres may also bemixed with pharmaceutically acceptable ingredients to create ointment orcream for topical applications.

In certain embodiments, the subject polymers are soluble in one or morecommon organic solvents for ease of fabrication and processing. Commonorganic solvents include such solvents as chloroform, dichloromethane,dichloroethane, 2-butanone, butyl acetate, ethyl butyrate, acetone,ethyl acetate, dimethylacetamide, N-methylpyrrolidone,dimethylformamide, and dimethylsulfoxide.

In addition, the polymer compositions may comprise blends of the polymerwith other biocompatible polymers or copolymers, so long as theadditional polymers or copolymers do not interfere undesirably with thebiocompatible, biodegradable and/or mechanical characteristics of thecomposition. Blends of the polymer with such other polymers may offereven greater flexibility in designing the precise release profiledesired for targeted drug delivery or the precise rate ofbiodegradability desired. Examples of such additional biocompatiblepolymers include other poly(phosphoesters), poly(carbonates),poly(esters), poly(orthoesters), poly(amides), poly(urethanes),poly(imino-carbonates), and poly(anhydrides).

Pharmaceutically acceptable polymeric carriers may also comprise a widerange of additional materials. Without being limited thereto, suchmaterials may include diluents, binders and adhesives, lubricants,disintegrants, colorants, bulking agents, flavorings, sweeteners, andmiscellaneous materials such as buffers and adsorbents, in order toprepare a particular medicated composition, with the condition that noneof these additional materials will interfere with the intended purposeof the subject composition.

Plasticizers and stabilizing agents known in the art may be incorporatedin polymers. In certain embodiments, additives such as plasticizers andstabilizing agents are selected for their biocompatibility.

A composition may further contain one or more adjuvant substances, suchas fillers, thickening agents or the like. In other embodiments,materials that serve as adjuvants may be associated with the polymermatrix. Such additional materials may affect the characteristics of thepolymer matrix that results. For example, fillers, such as bovine serumalbumin (BSA) or mouse serum albumin (MSA), may be associated with thepolymer matrix. In certain embodiments, the amount of filler may rangefrom about 0.1 to about 50% or more by weight of the polymer matrix, orabout 2.5, 5, 10, 25, 40 percent. Incorporation of such fillers mayaffect the biodegradation of the polymeric material and/or the sustainedrelease rate of any encapsulated substance. Other fillers known to thoseof skill in the art, such as carbohydrates, sugars, starches,saccharides, celluloses and polysaccharides, including mannitose andsucrose, may be used in certain embodiments.

In other embodiments, spheronization enhancers facilitate the productionof subject polymeric matrices that are generally spherical in shape.Substances such as zein, microcrystalline cellulose or microcrystallinecellulose co-processed with sodium carboxymethyl cellulose may conferplasticity to the subject compositions as well as implant strength andintegrity. In particular embodiments, during spheronization, extrudatesthat are rigid, but not plastic, result in the formation of dumbbellshaped implants and/or a high proportion of fines, and extrudates thatare plastic, but not rigid, tend to agglomerate and form excessivelylarge implants. In such embodiments, a balance between rigidity andplasticity is desirable. The percent of spheronization enhancer in aformulation depends on the other excipient characteristics and istypically in the range of 10-90% (w/w).

Buffers, acids and bases may be incorporated in the subject compositionsto adjust their pH. Agents to increase the diffusion distance of agentsreleased from the polymer matrix may also be included.

Disintegrants are substances which, in the presence of liquid, promotethe disruption of the subject compositions. Disintegrants are most oftenused in implants, in which the function of the disintegrant is tocounteract or neutralize the effect of any binding materials used in thesubject formulation. In general, the mechanism of disintegrationinvolves moisture absorption and swelling by an insoluble material.Examples of disintegrants include croscarmellose sodium and crospovidonethat, in certain embodiments, may be incorporated into the polymericmatrices in the range of about 1-20% of total matrix weight. In othercases, soluble fillers such as sugars (mannitol and lactose) may also beadded to facilitate disintegration of the subject compositions upon use.

Other materials may be used to advantage to control the desired releaserate of a therapeutic agent for a particular treatment protocol. Forexample, if the sustained release is too slow for a particularapplication, a pore-forming agent may be added to generate additionalpores in the matrix. Any biocompatible water-soluble material may beused as the pore-forming agent. They may be capable of dissolving,diffusing or dispersing out of the formed polymer system whereupon poresand microporous channels are generated in the system. The amount ofpore-forming agent (and size of dispersed particles of such pore-formingagent, if appropriate) within the composition should affect the size andnumber of the pores in the polymer system.

Pore-forming agents include any pharmaceutically acceptable organic orinorganic substance that is substantially miscible in water and bodyfluids and will dissipate from the forming and formed matrix intoaqueous medium or body fluids or water-immiscible substances thatrapidly degrade to water-soluble substances. Suitable pore-formingagents include, for example, sugars such as sucrose and dextrose, saltssuch as sodium chloride and sodium carbonate, and polymers such ashydroxylpropylcellulose, carboxymethylcellulose, polyethylene glycol,and polyvinylpyrrolidone. The size and extent of the pores may be variedover a wide range by changing the molecular weight and percentage ofpore-forming agent incorporated into the polymer system.

The charge, lipophilicity or hydrophilicity of any subject polymericmatrix may be modified by attaching in some fashion an appropriatecompound to the surface of the matrix. For example, surfactants may beused to enhance wettability of poorly soluble or hydrophobiccompositions. Examples of suitable surfactants include dextran,polysorbates and sodium lauryl sulfate. In general, surfactants are usedin low concentrations, generally less than about 5%.

Binders are adhesive materials that may be incorporated in polymericformulations to bind and maintain matrix integrity. Binders may be addedas dry powder or as solution. Sugars and natural and synthetic polymersmay act as binders. Materials added specifically as binders aregenerally included in the range of about 0.5%-15% w/w of the matrixformulation. Certain materials, such as microcrystalline cellulose, alsoused as a spheronization enhancer, also have additional bindingproperties.

Various coatings may be applied to modify the properties of thematrices. Three exemplary types of coatings are seal, gloss and entericcoatings. Other types of coatings having various dissolution or erosionproperties may be used to further modify subject matrices behavior, andsuch coatings are readily known to one of ordinary skill in the art.

The seal coat may prevent excess moisture uptake by the matrices duringthe application of aqueous based enteric coatings. The gloss coatgenerally improves the handling of the finished matrices. Water-solublematerials such as hydroxypropyl cellulose may be used to seal coat andgloss coat implants. The seal coat and gloss coat are generally sprayedonto the matrices until an increase in weight between about 0.5% andabout 5%, often about 1% for a seal coat and about 3% for a gloss coat,has been obtained.

Enteric coatings consist of polymers which are insoluble in the low pH(less than 3.0) of the stomach, but are soluble in the elevated pH(greater than 4.0) of the small intestine. Polymers such as EUDRAGIT,RohmTech, Inc., Malden, Mass., and AQUATERIC, FMC Corp., Philadelphia,Pa., may be used and are layered as thin membranes onto the implantsfrom aqueous solution or suspension or by a spray drying method. Theenteric coat is generally sprayed to a weight increase of about one toabout 30%, or about 10 to about 15% and may contain coating adjuvantssuch as plasticizers, surfactants, separating agents that reduce thetackiness of the implants during coating, and coating permeabilityadjusters.

The present compositions may additionally contain one or more optionaladditives such as fibrous reinforcement, colorants, perfumes, rubbermodifiers, modifying agents, etc. In practice, each of these optionaladditives should be compatible with the resulting polymer and itsintended use. Examples of suitable fibrous reinforcement include PGAmicrofibrils, collagen microfibrils, cellulosic microfibrils, andolefinic microfibrils. The amount of each of these optional additivesemployed in the composition is an amount necessary to achieve thedesired effect.

The subject polymers may be formed in a variety of shapes. For example,in certain embodiments, subject polymer matrices may be presented in theform of microparticles or nanoparticles. Such particles may be preparedby a variety of methods known in the art, including for example, solventevaporation, spray-drying or double emulsion methods.

The shape of microparticles and nanoparticles may be determined byscanning electron microscopy. Spherically shaped nanoparticles are usedin certain embodiments for circulation through the bloodstream. Ifdesired, the particles may be fabricated using known techniques intoother shapes that are more useful for a specific application.

In addition to intracellular delivery of a therapeutic agent, it alsopossible that particles of the subject compositions, such asmicroparticles or nanoparticles, may undergo endocytosis, therebyobtaining access to the cell. The frequency of such an endocytosisprocess will likely depend on the size of any particle.

In certain embodiments, solid articles useful in defining shape andproviding rigidity and structural strength to the polymeric matrices maybe used. For example, a polymer may be formed on a mesh or other weavefor implantation. A polymer may also be fabricated as a stent or as ashunt, adapted for holding open areas within body tissues or fordraining fluid from one body cavity or body lumen into another. Further,a polymer may be fabricated as a drain or a tube suitable for removingfluid from a post-operative site, and in some embodiments adaptable foruse with closed section drainage systems such as Jackson-Pratt drainsand the like familiar in the art.

The mechanical properties of the polymer may be important for theprocessability of making molded or pressed articles for implantation.For example, the glass transition temperature may vary widely but mustbe sufficiently lower than the temperature of decomposition toaccommodate conventional fabrication techniques, such as compressionmolding, extrusion or injection molding.

In certain embodiments, the polymers and blends, upon contact with bodyfluids, undergo gradual degradation. The life of a biodegradable polymerin vivo depends, among other things, upon its molecular weight,crystallinity, biostability, and the degree of crosslinking. In general,the greater the molecular weight, the higher the degree ofcrystallinity, and the greater the biostability, the slowerbiodegradation will be.

If a subject polymer matrix is formulated with a therapeutic agent,release of such an agent for a sustained or extended period as comparedto the release from an isotonic saline solution generally results. Suchrelease profile may result in prolonged delivery (over, say 1 to about4,000 hours, or alternatively about 4 to about 1500 hours) of effectiveamounts (e.g., about 0.00001 mg/kg/hour to about 10 mg/kg/hour) of theagent associated with the polymer.

A variety of factors may affect the desired rate of hydrolysis ofpolymers, the desired softness and flexibility of the resulting solidmatrix, rate and extent of bioactive material release. Some of suchfactors include: the selection of the various substituent groups, suchas the phosphate group making up the linkage in the polymer backbone (oranalogs thereof), the enantiomeric or diastereomeric purity of themonomeric subunits, homogeneity of subunits found in the polymer, andthe length of the polymer. For instance, the present disclosurecontemplates heteropolymers with varying linkages, and/or the inclusionof other monomeric elements in the polymer, in order to control, forexample, the rate of biodegradation of the matrix.

To illustrate further, a wide range of degradation rates may be obtainedby adjusting the hydrophobicities of the backbones or side chains of thepolymers while still maintaining sufficient biodegradability for the useintended for any such polymer. Such a result may be achieved by varyingthe various functional groups of the polymer. For example, thecombination of a hydrophobic backbone and a hydrophilic linkage producesheterogeneous degradation because cleavage is encouraged whereas waterpenetration is resisted. In another example, it is expected that use ofsubstituent on phosphate in the polymers that is lipophilic, hydrophobicor bulky group would slow the rate of degradation. For example, it isexpected that conversion of the phosphate side chain to a morelipophilic, more hydrophobic or more sterically bulky group would slowdown the rate of biodegradation. Thus, release is usually faster frompolymer compositions with a small aliphatic group side chain than with abulky aromatic side chain.

One protocol generally accepted in the field that may be used todetermine the release rate of any therapeutic agent or other materialloaded in the polymer matrices involves degradation of any such matrixin a 0.1 M PBS solution (pH 7.4) at 37° C., an assay known in the art.For purposes of the present disclosure, the term “PBS protocol” is usedherein to refer to such protocol.

In certain instances, the release rates of different polymer systems maybe compared by subjecting them to such a protocol. In certain instances,it may be necessary to process polymeric systems in the same fashion toallow direct and relatively accurate comparisons of different systems tobe made. Such comparisons may indicate that any one polymeric systemreleases incorporated material at a rate from about 2 or less to about1000 or more times faster than another polymeric system. Alternatively,a comparison may reveal a rate difference of about 3, 5, 7, 10, 25, 50,100, 250, 500 or 750. Even higher rate differences are contemplated bythe present disclosure and release rate protocols.

In certain embodiments, when formulated in a certain manner, the releaserate for polymer systems may present as mono- or bi-phasic. Release ofany material incorporated into the polymer matrix, which is oftenprovided as a microsphere, may be characterized in certain instances byan initial increased release rate, which may release from about 5 toabout 50% or more of any incorporated material, or alternatively about10, 15, 20, 25, 30 or 40%, followed by a release rate of lessermagnitude.

The release rate of any incorporated material may also be characterizedby the amount of such material released per day per mg of polymermatrix. For example, in certain embodiments, the release rate may varyfrom about 1 ng or less of any incorporated material per day per mg ofpolymeric system to about 5000 or more ng/day·mg.

Alternatively, the release rate may be about 10, 25, 50, 75, 100, 125,150, 175, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800 or 900ng/day·mg. In still other embodiments, the release rate of anyincorporated material may be 10,000 ng/day·mg or even higher. In certaininstances, materials incorporated and characterized by such release rateprotocols may include therapeutic agents, fillers, and other substances.

In another aspect, the rate of release of any material from any polymermatrix may be presented as the half-life of such material in the suchmatrix.

In addition to the embodiment involving protocols for in vitrodetermination of release rates, in vivo protocols, whereby in certaininstances release rates for polymeric systems may be determined in vivo,are also contemplated by the present disclosure. Other assays useful fordetermining the release of any material from the polymers of the presentsystem are known in the art.

7. Combinations of Controlled-Release Composition and Therapeutic Agent

In some embodiments, for delivery of a therapeutic agent, the agent isadded to the polymer composition. A variety of methods are known in theart for encapsulating a biologically active substance in a polymer. Forexample, the agent or substance may be dissolved to form a homogeneoussolution of reasonably constant concentration in the polymercomposition, or it may be dispersed to form a suspension or dispersionwithin the polymer composition at a desired level of “loading” (grams ofbiologically active substance per grams of total composition includingthe biologically active substance, usually expressed as a percentage).

In part, a polymer composition useful in the treatment of joint pain,inflammation, infection, or other problems, includes both: (a) atherapeutic agent, and (b) a biocompatible and optionally biodegradablepolymer, such as one having the recurring monomeric units shown in oneof the foregoing formulas, or any other biocompatible polymer mentionedabove or known in the art. In certain embodiments in which the subjectcomposition will be used to treat pain, the agent is an analgesic oranesthetic; for inflammation, a steroidal or non-steroidalantiinflammatory agent; and for infection, an antimicrobial effectiveagainst the pathogen(s) of concern, such as an antibiotic, antifungal,antimycotic, antimalarial, antimycobacterial, antiparasitic, orantiviral. In some embodiments, the subject compositions encapsulatemore than one agent for treatment of one or more joint problems.

8. Delivery Systems

In its simplest form, a delivery system for a therapeutic agent fortreatment of a joint problem consists of a dispersion of such an agentinto one of the polymers described above. In other embodiments, anarticle is used for implantation, injection, or otherwise placed totallyor partially within the body, the article comprising a composition fortreatment of a joint problem. It may be particularly important that suchan article result in minimal tissue irritation when applied to,implanted in or injected into vascularized tissue, hypovascularizedpost-operative tissue or tissue exposed to previous radiation that ispart of a joint. In certain embodiments, a solid, flowable or fluidarticle is inserted within an anatomic area by implantation, injection,endoscopy or otherwise being placed within an anatomic area of thesubject being treated for a joint problem.

As a structural medical device, the polymer compositions provide a widevariety of physical forms having specific chemical, physical andmechanical properties suitable for insertion into an anatomic area

Biocompatible delivery systems and articles thereof, may be prepared ina variety of ways known in the art. The subject polymer may be meltprocessed using conventional extrusion or injection molding techniques,or these products may be prepared by dissolving in an appropriatesolvent, followed by formation of the device, and subsequent removal ofthe solvent by evaporation or extraction, e.g., by spray drying. Bythese methods, the polymers may be formed into articles of almost anysize or shape desired, for example, implantable solid discs or wafers orinjectable rods, microspheres, or other microparticles. Typical medicalarticles also include such as implants as laminates for degradablefabric or coatings to be placed on other implant devices.

In one embodiment, certain polymer compositions may be used to form asoft, drug-delivery “depot” that can be administered as a liquid, forexample, by injection, but which remains sufficiently viscous tomaintain the drug within the localized area around the injection site.By using a polymer composition in flowable form, even the need to makean incision can be eliminated. In any event, the flexible or flowabledelivery “depot” will adjust to the shape of the space it occupieswithin the body with a minimum of trauma to surrounding tissues.

When the polymer composition is flexible or flowable, it may be placedanywhere within the body, including into an anatomic area of a joint. Itmay be inserted into the anatomic area either through an open surgicalwound, under direct or indirect vision, or through any of the accessdevices routinely used in the art to enter such areas, for example,indwelling or acutely-inserted catheters, needles, drains,superselective angiography means and the like. A flowable or fluidpolymer may be adapted for mixing with the transudate or exudate foundwithin or expected to gather within the anatomic area A flowable orfluid polymer may be instilled in an anatomic area during surgery onorgans or structures therein to decrease the likelihood of recurrentdisease when there is a high risk for its development. In certainembodiments, a polymer composition may also be incorporated in accessdevices so that a therapeutic agent is released into the anatomic areawithin which the access device resides. The polymer composition may alsobe used to produce coatings for other solid implantable devices fortreatment of joint problems.

Once a system or implant article is in place, it should remain in atleast partial contact with a biological fluid, such as blood, tissuefluid, lymph, or secretions from organ surfaces or mucous membranes, andthe like to allow for sustained release of any encapsulated therapeuticagent, e.g., a therapeutic agent.

These examples of the clinical utility of the disclosed devices andmethods have been provided for illustrative purposes only. Otherexemplary utilizations will be apparent to practitioners of ordinaryskill in the art using no more than routine experimentation.

EXAMPLES Example 1

In one example, the drug carrier is provided as a cartridge. The drugmay be loaded into the cartridge as a powder, compressed solid, or asgranules without a polymer mixture. Alternative the drug may be combinedwith any suitable biocompatible, biodegradable polymer. Examples of suchbiocompatible biodegradable polymers useful include: hydroxyaliphaticcarboxylic acids, either homo- or copolymers, such as polylactic acid,polyglycolic acid, polylactic glycolic acid; polysaccharides such ascellulose or cellulose derivatives such as ethyl cellulose, cross-linkedor uncross-linked sodium carboxymethyl cellulose, sodiumcarboxymethylcellulose starch, cellulose ethers, cellulose esters suchas cellulose acetate, cellulose acetate phthallate, hydroxypropylmethylcellulose phthallate and calcium alginate, polypropylene, polybutyrates,polycarbonate, acrylate polymers such as polymethacrylates,polyanhydrides, polyvalerates, polycaprolactones such aspoly-.epsilon.-caprolactone, polydimethylsiloxane, polyamides,polyvinylpyrollidone, polyvinylalcohol phthallate, waxes such asparaffin wax and white beeswax, natural oils, shellac, zein, hyaluronicacid, or a mixture thereof.

Example 2

In one exemplary embodiment, a sustained release device includes apolymeric matrix or liposome from which drug is released by diffusionand/or degradation of the matrix. The release pattern is usuallyprincipally determined by the matrix material, as well as by the percentloading, method of manufacture, type of drug being administered and typeof device, for example, microsphere. A major advantage of abiodegradable controlled release system over others is that it does notrequire the surgical removal of the drug depleted device, which isslowly degraded and absorbed by the patient's body, and ultimatelycleared along with other soluble metabolic waste products.

Systemic anesthetics such as methoxyflurane, have been incorporated intoliposomes and lecithin microdroplets, for example, as described byHaynes, et al., Anesthesiology 63:490-499 (1985). To date, the liposomeand lecithin preparations have not been widely applied in clinical orlaboratory practice, because of their inability to provide denseblockade for a prolonged period of time (i.e., three or more days) in asafe and controlled manner. The lecithin microdroplets and liposomesdegrade or are phagocytized too rapidly, in a matter of hours. Otherlipid based devices, formed in combination with polymer, for release oflocal anesthetics are described by U.S. Pat. No. 5,188,837 to Domb.Researchers have also explored the use of polymer microspheresconstructed of poly-lactic-glycolic acid combinations for the release oflocal anesthetics and antiinflammatories such as bupivicaine anddexamethasone with some initial promise in nerve blockade (Drager et.al., Anesthesiology 89(4):969-979 (1998)).

Example 3

A biocompatible intra-articular device size for implantation within ajoint to continuously deliver a drug within the joint for a period of atleast several weeks may include an outer bone anchor construct and aninner core consisting of a drug/polymer reservoir. The drug/polymerreservoir elutes a drug that dissolves in joint fluid through asemipermeable membrane at the synovial fluid interface. The device isimplanted in a non-loaded but intra-articular portion of the joint wheresynovial fluid agitation across the semi-permeable membrane promotesdrug elution.

Example 4

Exemplary sustained release compositions include poly-glycolic acid,polylactic acid, polyester, collagen, a hydrogel, hyaluronic acid, andcombinations of these.

Example 5

Exemplary therapeutic agents include bupivicaine, lidocaine,dexamethasone, a non-steroidal antiinflammatory agent, an antibiotic, animmunomodulator, a bone morphogenic protein, a cytokine, a growthfactor, a vascular endothelial growth factor, and combinations of these.

Example 6

An exemplary device may be affixed in the joint implantation into apre-drilled bone tunnel. In such an embodiment, the outer shell of thedevice includes a bone anchor design with axially aligned andconcentrically spaced barbs.

Example 7

In some embodiments, a sustained release device for a joint is deployedin an ambulatory setting, such as an office-based ambulatory surgicalsuite. The specific point of insertion will be identified usingorthogonal radiography or stereotactic CT scanning. An injector gun willbe used to pre-drill and then insert the device into the bone tunnel.

Example 8

In a typical procedure, the device may be inserted in a minor procedureor ambulatory surgical setting via a percutaneous delivery gun, using aninsertion device (such as depicted in FIG. 14). The specific targetattachment zone can be identified by palpation of anatomic landmarksand/or radiographically by orthogonal plain radiographs, computerizedtomographic imaging, or three dimensional computerized tomographicimaging and localization, or by other localization techniques. Localanesthetic can be administered into the skin and subcutaneous tissuesand into the synovium. A stab incision may be made in the skin. Bluntdissection may then be carried down through subcutaneous tissue. Acannulated trochar may then be used to penetrate the joint capsule. Thetrochar may be advanced to the target delivery site identifiedpreviously. The delivery gun or insertion device may be placed into thecannula of the trochar. A bone tunnel may be pre-drilled or the implantdirectly inserted into the bone of the attachment zone. If the devicehas outer threads, such as shown in FIG. 11, it may be seated by usingthose self tapping and self boring outer threads of the stage. Thesurgical wound may then be closed using conventional techniques.

Example 9

A drug insert may be replaced by a minor surgical procedure. Surgicalaccess may be gained to the device—i.e., anesthesia, incision,dissection, and capsule penetration using a cannulated trocar. A druginsert retrieval device may be placed in the trocar and advanced to thedevice. The drug insert may be impaled or otherwise attached to theretrieval device, which may then be withdrawn to remove the drug insert.A replacement drug insert, mounted on a drug insert placement device(which may be the same as the drug insert retrieval device), may then beplaced in the cannula and advanced to the attached drug delivery device.

Example 10

A drug insert can include a polymer solution/drug mixture having apolymer and a co-dissolved or suspended drug. This drug/polymer insertmay be constructed by forming a polymer solution/drug mixture includinga polymer-dissolved in an organic solvent and a co-dissolved orsuspended drug and then removing the solvent from the polymersolution/drug mixture to form the solid polymer/drug matrix. The polymercan be any biocompatible polymer, such as poly(lactic acid) or apoly(lactic acid-co-glycolic acid) copolymer. The drug can be atherapeutic, prophylactic or diagnostic agent, such as a protein,nucleic acid or small organic molecule.

Example 11

A drug insert may include dexamethasone and polylactic glycolic acid.

Example 12

A drug insert may include gentamycin and polylactic glycolic acid.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and practices described herein. Such equivalents areintended to be encompassed by the following claims.

1. A method of intra-articular drug delivery, comprising: selecting anattachment zone in a synovial joint; and affixing a drug release devicein the attachment zone, the drug release device comprising a baseaffixable in the attachment zone, a sustained-release drug carrier, anda drug, the device positioned so that the device releases the drug intothe synovial fluid of the synovial joint, and so that agitation of thesynovial fluid facilitates elution of the drug from the drug releasedevice.
 2. The method of claim 1, wherein the attachment zone comprisesa non-articulating portion of bone and/or cartilage within the synovialjoint.
 3. The method of claim 2, further comprising removing the boneand/or cartilage in the attachment zone to create a void, and soinserting the drug release device into the void that at least onesurface of the drug release device is in communication with the synovialfluid.
 4. The method of claim 3, wherein the drug release device is soinserted that its surface in communication with the synovial fluid isabout flush with surrounding bone and/or cartilage.
 5. The method ofclaim 2, wherein the attachment zone comprises a band of bone and/orcartilage adjacent to an articulating surface within the synovial joint.6. The method of claim 5, wherein the band extends from about 0.5millimeters to about 1 centimeter away from the articulating surface. 7.The method of claim 5, further comprising removing the bone and/orcartilage in the attachment zone to create a void, and so inserting thedrug release device into the void that at least one surface of the drugrelease device is in communication with the synovial fluid.
 8. Themethod of claim 7, wherein the drug release device is so inserted thatits surface in communication with the synovial fluid is about flush withsurrounding bone and/or cartilage.
 9. The method of claim 1, wherein thesynovial joint is a hip joint, and the attachment zone comprises anon-articulating portion of bone and/or cartilage within the hip. 10.The method of claim 9, wherein the attachment zone comprises a band ofbone and/or cartilage adjacent to at least one of a femoral head, and anacetabulum.
 11. The method of claim 1, wherein the synovial joint is aknee joint, and the attachment zone comprises a non-articulating portionof bone and/or cartilage within the knee.
 12. The method of claim 11,wherein the attachment zone comprises a band of bone and/or cartilageadjacent to at least one of a tibial plateau, a femoral condyle, apatellofemoral area, the medial rim of a femoral trochlea, the lateralrim of a femoral trochlea, and the periphery of an intercondylar notch.13. The method of claim 1, wherein the synovial joint is a shoulderjoint, and the attachment zone comprises a non-articulating portion ofbone and/or cartilage within the shoulder.
 14. The method of claim 13,wherein the attachment zone comprises a band of bone and/or cartilageadjacent to at least one of the anatomical neck of a humerus, a glenoidcavity, and a glenoid neck.
 15. The method of claim 1, wherein thesynovial joint is an arthroplastic joint comprising at least oneprosthesis, and the attachment zone comprises a non-articulating portionof bone and/or cartilage within the joint.
 16. The method of claim 15,wherein the attachment zone comprises a band of bone and/or cartilageadjacent to the at least one prosthesis.
 17. The method of claim 1,wherein the drug release device is forcefully injected by gun.
 18. Themethod of claim 1, wherein the drug release device comprises threads onits outer surface, and the drug release device is affixed by drilling ahole in the attachment zone and screwing the drug release device intothe hole.
 19. A method of intra-articular drug delivery, comprising:step for selecting a para-articular attachment zone in a synovial joint;step for creating a void in the para-articular attachment zone; and stepfor implanting in the void a drug-release means for sustainedlyreleasing a drug into the synovial fluid of the synovial joint.
 20. Asustained-release intra-articular drug delivery device, comprising: abase, so sized and shaped as to be affixable in an attachment zone of asynovial joint; and a sustained-release drug carrier coupled to thebase, the carrier including a drug, the carrier so formed as to elutethe drug into synovial fluid, upon implantation of the device in ajoint, sufficient to sustain a therapeutically effective concentrationof the drug in the synovial fluid for at least 8 hours.